Pathological complete response following neoadjuvant chemotherapy with PD-1 inhibitor for locally advanced pancreatic cancer: case report

Introduction

As the seventh leading cause of cancer death worldwide and the third leading cause of death in the United States (1), some studies even predict that pancreatic cancer will surpass breast, prostate and colorectal cancers as the second leading cause of cancer-related deaths (2,3). Although surgery is the primary approach of curing pancreatic cancer, less than 20% of patients are diagnosed with surgically resectable status (4), which indicates that multiple non-surgical treatments are indispensable. Due to the unique genetic background, resistance to chemotherapy drugs, and the “cold” tumor microenvironment (TME) of pancreatic cancer, monotherapy is insufficient for treating, and multi-agent chemotherapy may hold the key to achieving breakthroughs in addressing some challenges (5).

Currently, studies demonstrated that FOLFIRINOX or modified FOLFIRINOX and gemcitabine with albumin-bound paclitaxel, which are the two primary chemotherapy regimens for pancreatic cancer recommended by National Comprehensive Cancer Network (NCCN) guidelines, possess their own unique advantages and disadvantages (6,7). And the chemoresistance in pancreatic cancer arising from tumor genomic mutations, metabolic reprogramming and epithelial-mesenchymal transition is also a key challenge to be addressed (8). Despite the poor efficacy of immunotherapy in the treatment of pancreatic cancer when used alone, there are still numerous ongoing basic and clinical trials targeting pancreatic cancer immunity. The combination of immune checkpoint inhibitors and standard chemotherapy demonstrates superior efficacy in terms of prolonging disease-free survival for patients (9), as well as augmenting the CD8⁺ T cell to T-regulatory cells (T-regs) ratio (10). Currently, there are many basic studies aimed at discovering new target molecules to enhance the therapeutic effects of immunosuppressants such as programmed cell death protein 1 (PD-1). For instance, the absence of SIN3B molecules remodels the microenvironment of pancreatic tumors via the C-X-C motif chemokine ligand 9/10 (CXCL9/10)-C-X-C motif chemokine receptor 3 (CXCR3) axis, specifically facilitating the infiltration of CD8+ T cells and augmenting the response to anti-PD-1 therapy (11). The combination of IOX2 [membrane metalloendopeptidase (MME) + cancer-associated fibroblasts (CAF) inhibitor] with AG (albumin-bound paclitaxel with gemcitabine) regimen and anti-PD-1 therapy has demonstrated promising antitumor effects (12). These studies are all centered on anti-PD-1 immunotherapy, aiming to identify novel strategies to enhance its efficacy. The potential for incorporating immunotherapy as a standard treatment approach, along with the determination of the optimal treatment regimen and timing, requires further investigation.

In this article, we present two cases of locally advanced pancreatic cancer in which neoadjuvant chemotherapy (gemcitabine with albumin-bound paclitaxel) was administered in combination with a PD-1 inhibitor (tislelizumab), resulting in the opportunity for surgical intervention. Notably, one patient exhibited a pathological complete response. This can serve as a valuable reference for studies on the treatment regimens and the application of neoadjuvant chemotherapy. And it is anticipated that the discovery of these cases can be further studied and confirmed in larger clinical trials, giving a new hope for the treatment of pancreatic cancer patients. We present this article in accordance with the CARE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-549/rc).

Case presentation

Case 1

The patient was a 58-year-old male, who complained of persistent upper abdominal discomfort for more than 2 months without obvious incentives. He had a history of smoking and alcohol consumption for over 30 years, yet he did not have any specific chronic illnesses or family history of cancer.

When he was admitted to hospital, the enhanced computed tomography (CT) showed a 25 mm × 15 mm irregular hypodense lesion with mild enhancement within the neck of pancreas (Figure 1). The invasion of the portal vein, splenic vein and superior mesenteric vein was presented. Due to the involvement of the lower segment of common bile duct, the pancreatic duct, intrahepatic and extrahepatic bile ducts were mildly dilated. The patient underwent endoscopic ultrasonography with fine-needle aspiration examination, and the pathology report revealed a diagnosis of pancreatic cancer. The patient presented without jaundice symptoms, and the initial blood biochemistry analysis revealed alanine aminotransferase (ALT) level of 141 U/L (reference range, ≤41 U/L), and aspartate aminotransferase (AST) level of 80 U/L (reference range, ≤40 U/L) (Figure 2A). The tumor markers indicated a slightly elevated level of carbohydrate antigen 19-9 (CA19-9) at 60.3 U/mL (reference range, ≤34.0 U/mL), carbohydrate antigen 125 (CA125) at 47.7 U/mL (reference range, ≤35.0 U/mL) (Figure 2B).

Figure 1 Enhanced CT images during neoadjuvant chemotherapy after diagnosis of Case 1 patient. The first column corresponds to the arterial phase, the middle column represents the portal venous phase, and the last column depicts the delayed venous phase. C3 represents CT images taken after three cycles of neoadjuvant chemotherapy, while C5 represents those taken after five cycles. CT, computed tomography.

Figure 2 Alterations in biochemical and tumor parameters observed during the patient’s visit in Case 1. (A) The changing trends of blood biochemistry throughout the treatment process, including ALT, AST, and total bilirubin. (B) Trends in tumor markers, including CA19-9, CA125, and CEA. AST, aspartate aminotransferase; ALT, alanine aminotransferase; CA19-9, carbohydrate antigen 19-9; CA125, carbohydrate antigen 125; CEA, carcinoembryonic antigen.

Subsequently, the patient received gemcitabine plus albumin-bound paclitaxel combined with PD-1/programmed death-ligand 1 (PD-L1) inhibitor therapy from January, 2022. The albumin-bound paclitaxel is injected intravenously 125 mg/m² (days 1 and 8); while gemcitabine 1,000 mg/m² (days 1 and 8) approximately every 3 weeks. And the PD-1/PD-L1 inhibitor (tislelizumab) is given 200 mg intravenously every 3 weeks. At the end of six complete cycles (approximately 5 months before surgery), the tumor marker CA19-9 decreased to 13.1 U/mL (Figure 2B); and enhanced CT showed that the tumor was slightly smaller than before (14 mm × 10 mm) (Figure 3).

Figure 3 Enhanced CT images of the patient in Case 1 after six cycles of neoadjuvant chemotherapy and during late follow-up. The first column corresponds to the arterial phase, the middle column represents the portal venous phase, and the last column depicts the delayed venous phase. CT, computed tomography.

Afterwards, the patient accepted radical pancreaticoduodenectomy; and the pancreatic tissue was found severely fibrotic during the surgery. The blood loss was around 1,200 mL, and transient liver failure occurred after the operation. The postoperative histopathological examination showed complete response with a small amount of residual high-grade intraepithelial neoplasia and extensive fibrosis and hyaline degeneration of the pancreas (Figure 4).

Figure 4 Postoperative pathological results of patient in Case 1. The postoperative histopathological examination showed complete response with a small amount of residual high-grade intraepithelial neoplasia and extensive fibrosis and hyaline degeneration of the pancreas. Hematoxylin and eosin staining, magnification: left panel ×100, right panel ×100.

The patient had the first postoperative re-visit in September 2022, and the enhanced CT showed pancreaticoduodenectomy surgery changes, and no metastases were found (Figure 3). The results of tumor marker test showed mild elevation of carcinoembryonic antigen (CEA) and CA125 (CEA 5.8 ng/mL, CA125 45.0 U/mL), while the result of CA19-9 was normal (CA19-9 19.5 U/mL) (Figure 2B). The patient underwent continued chemotherapy and immunotherapy at his local hospital, following the established regimen, beyond November 2022.

After the operation, the genetic test found that the patient had KRAS mutation (c.35G>T, p.G12V); and no pathogenic variants in other genes including EGFR, BRCA1, BRCA2 or PALB2 were identified. The results of chemosensitivity test showed that the patient had better response to capecitabine, gemcitabine and docetaxel, which was compatible with our chemotherapy regimen. For PD-L1 expression test results: the tumor proportion score (TPS) of PD-L1 was 2%; and the combined positive score (CPS) was 5. The tumor microsatellite instability (MSI) value was 0.125.

After the surgery, the patient said, “The chemotherapy and immunotherapy caused me significant nausea and weakness, particularly physical weakness, which at times has been overwhelming and has even led me to contemplate giving up. During the surgical procedure, I experienced considerable fear; fortunately, I persevered and am still alive today. I extend my heartfelt gratitude to all the doctors for their attentive care.” The primary adverse effects observed were neutropenia, mild to moderate anemia, and a slight reduction in albumin levels. Transient thrombocytopenia was noted during the initial stages of treatment, and while vomiting occurred, it was not severe.

Case 2

The patient is a 60-year-old male who presented with intermittent abdominal pain for over 2 months of unknown etiology. He has a history of hypertension spanning more than a decade, which is currently well-managed with oral nifedipine. Additionally, he has been a smoker for 40 years but denies any alcohol consumption or family history of cancer.

On admission, an enhanced focus around 31 mm × 25 mm was observed in the pancreatic head area on the enhanced CT scan, raising suspicion of pancreatic cancer (Figure 5). The demarcation with the descending part of the duodenum appeared indistinct, while the surrounding fat density was increased and hazy. Retroperitoneal lymph nodes were also blurred and encircled the origin of the superior mesenteric artery. Fine needle aspiration examination was performed on the patient, and subsequent pathological analysis confirmed a diagnosis of pancreatic cancer. Initial blood biochemical analysis revealed bilirubin levels at 5.8 µmol/L, ALT levels at 17 U/L, and AST levels at 20 U/L (Figure 6A). Tumor markers demonstrated significant elevation with CA19-9 levels measuring at 645.3 U/mL (Figure 6B).

Figure 5 Enhanced CT images of Case 2 patient. The first column corresponds to the arterial phase, the middle column represents the portal venous phase, and the last column depicts the delayed venous phase. C3 represents CT images taken after three cycles of neoadjuvant chemotherapy. CT, computed tomography.

Figure 6 Alterations in biochemical and tumor parameters observed during the patient’s visit in Case 2. (A) The changing trends of blood biochemistry throughout the treatment process, including ALT, AST, and total bilirubin. (B) Trends in tumor markers, including CA19-9, CA125, and CEA. AST, aspartate aminotransferase; ALT, alanine aminotransferase; CA19-9, carbohydrate antigen 19-9; CA125, carbohydrate antigen 125; CEA, carcinoembryonic antigen.

Subsequently, in December 2023, the patient commenced receiving the identical treatment regimen as previously described. Following completion of 3 cycles of treatment, an enhanced CT scan was performed again, revealing a reduction in lesion size to dimensions measuring 25 mm × 18 mm, accompanied by decreased involvement of surrounding lymph nodes and retroperitoneal lymph nodes (Figure 5). At the conclusion of 5 cycles (approximately 4 months before surgery), tumor marker CA19-9 levels declined to 53.86 U/mL (Figure 6B). Enhanced CT imaging demonstrated that the tumour exhibited shrinkage, measuring now at dimensions measuring 21 mm × 15 mm (Figure 5).

The patient also underwent radical pancreaticoduodenectomy; postoperative histopathological examination showed moderately to poorly differentiated ductal adenocarcinoma (Figure 7), although he did not achieve complete pathological remission like the previous patient, he still received smooth surgical treatment. The content, including genetic testing and chemotherapy sensitivity testing, is voluntarily and self-funded by the patient, as the patient did not undergo these tests due to his financial circumstances. At present, he recovered fairly well. He continued to receive chemotherapy in the local hospital. According to the patient’s description, he was very depressed for suffering from pancreatic cancer. After the surgery, the patient said, “The primary discomfort associated with this treatment was nausea. Each time I underwent the treatment, I experienced severe vomiting and was unable to eat at all. Although I felt fatigued, I was still able to rise and engaged in appropriate activities. I am grateful for the opportunity to have completed the surgery following this treatment.” The primary adverse effects observed include neutropenia, severe vomiting, and mild anemia. No additional serious adverse effects were noted.

Figure 7 Postoperative pathological results of patient in Case 2. The postoperative histopathological examination revealed moderately to poorly differentiated ductal adenocarcinoma of the pancreas. Hematoxylin and eosin staining, magnification: left panel ×200, right panel ×400.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). The research involving human participants were reviewed and approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (No. TJ-IRB20190418). Written informed consent was obtained from the patients for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Pancreatic cancer has long been recognized as one of the most aggressive malignancies, and its global burden has been climbing sharply in the last decade (13). The lack of constructive breakthroughs in the diagnosis and treatment of pancreatic cancer may contribute to the almost equal mortality and morbidity rates observed (14). In this article, we present two cases of locally advanced pancreatic cancer in which neoadjuvant chemotherapy (gemcitabine with albumin-bound paclitaxel) was administered in combination with a PD-1 inhibitor (tislelizumab), resulting in the opportunity for surgical intervention. Notably, one patient exhibited a pathological complete response. This may provide some reference value for the treatment of pancreatic cancer, and also calls for further research and clinical trials to identify more innovative and sensitive molecular markers or assays, as well as effective treatment options that can enhance control over this disease.

Currently, the first-line recommended chemotherapy treatments turn out to be FOLFIRINOX or modified FOLFIRINOX and gemcitabine with albumin-bound paclitaxel, and the optimal regimen is still being explored. Gemcitabine (2’,2’-difluoro 2’-deoxycytidine, dFdC), an analogue of cytosine arabinoside (Ara-C), is transported into cells by human nucleoside transporters (hNTs) on the cell membrane, and phosphorylated to gemcitabine monophosphate (dFdCMP) by deoxycytidine kinase (dCK), and subsequently converted to gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP), which exert the main biological effects (15). dFdCTP is a deoxyribonucleic acid (DNA) polymerase inhibitor that competes with dCTP for incorporation into the DNA strand. DNA polymerase is unable to remove the incorporated dFdCTP, rendering the extended DNA strand unrepairable, thereby inhibiting DNA synthesis. In addition, dFdCDP exerts inhibitory effects on ribonucleic acid reductase and suppresses the biosynthesis of dCTP, thereby synergizing with dFdCTP to ultimately induce apoptosis. Paclitaxel induces and promotes microtubule polymerization and disrupts the dynamic balance between microtubulin and microtubulin dimers, which leads to mitotic arrest of cancer cells and exerts anti-cancer effects (16). The albumin-bound paclitaxel formulation addresses the issue of paclitaxel’s water insolubility and circumvents the toxic side effects that were once associated with its solubilization using Cremophor EL (BASF SE, Ludwigshafen, Germany). Albumin-bound paclitaxel may enhance the intratumoral penetration of gemcitabine by depleting stromal barriers in the TME, and it may also prolong the retention of gemcitabine within tumors by downregulating cytidine deaminase (CDA), a key enzyme responsible for gemcitabine inactivation (17,18). Nevertheless, tumor cells may develop resistance to chemotherapy drugs through innate or acquired changes, which can pose challenges for the treatment of pancreatic cancer. In addition to hNTs, ATP-binding cassette (ABC) transporter proteins can also be involved in chemoresistance by transporting gemcitabine extracellularly and reducing intracellular concentrations in tumor cells (19). Yuan et al. discovered that the expression of SPARC was downregulated by the SOX8 gene, leading to a decrease in the uptake of albumin-bound paclitaxel into pancreatic cancer cells (20). Research into the mechanisms of action and resistance pathways of chemotherapeutic drugs can significantly aid in the treatment of pancreatic cancer.

In addition to chemotherapy, immunotherapy is also a crucial treatment modality for solid tumors. In 2007, Nomi et al. conducted the pioneering investigation on the expression of PD-L1 and PD-L2 in several pancreatic cancer tissues, and revealed a significant correlation between PD-L1 expression in tumors and postoperative prognosis (21). Numerous studies have demonstrated the significant efficacy of the PD-1/PD-L1 pathway in various clinical trials and its successful application in treating diverse types of cancers, including Hodgkin’s lymphoma, melanoma, non-small-cell lung cancer, gastric cancer, etc., whereas its application in pancreatic cancer is still in the exploratory stage (22,23). In a randomized phase 2 trial, Padrón et al. evaluated the efficacy of nivolumab (anti-PD-1) and/or sotigalimab (CD40 agonist antibody) in combination with gemcitabine/nab-paclitaxel for patients with metastatic pancreatic ductal adenocarcinoma (PDAC) (24). Among the 105 patients included in the efficacy analysis, the primary endpoint of 1-year overall survival (OS) was achieved by 57.7% in the nivo/chemo group, 48.1% in the sotiga/chemo group, and 41.3% in the sotiga/nivo/chemo group. Furthermore, it was observed that survival following nivo/chemo treatment correlated with a less immunosuppressive TME and a higher baseline count of activated antigen-experienced circulating T cells. A randomized phase II trial conducted by Chen et al. demonstrated that among patients with locally advanced pancreatic cancer, the group receiving mFOLFIRINOX in combination with an anti-PD-1 antibody exhibited a higher resection rate (37.1% vs. 48.0%) (25). Nevertheless, by reason of the distinctive intrinsic factors or immunosuppressive TME of pancreatic cancer, drugs related to immunotherapy [such as medications for cytotoxic T lymphocyte protein 4 (CTLA4) or PD-1] have no significant effect when used alone (8,23,26,27). The TME consists of substrates, infiltrating immune cells, mesenchymal cells, and active mediators that co-exist with the tumor cells can largely affect the function of the tumor cells themselves and the immune cells. Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs) and T-regs present in TEM facilitate immune evasion of tumor cells by restraining CD8 T-cell activity (23). Pancreatic stellate cells (PSCs), a type of pancreatic stromal cells, secrete deoxycytidine (dC) which competes with gemcitabine for dCK and thus mediates drug resistance in pancreatic cancer (28). The integrated approach of increasing immunogenicity while simultaneously addressing the immunosuppressive TME may render pancreatic cancer more amenable to immunotherapy, thereby facilitating its broader application in the treatment of this malignancy (29).

KRAS gene that a homologue of Kirsten ras oncogene from RAS family, encodes the KRAS protein belonging to a small guanosine triphosphatase (GTPase) superfamily. In physiological conditions, Ras proteins transform between an active (bound to GTP) and an inactive [bound to guanosine diphosphate (GDP)] state to activate some oncogenic pathways, like mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K). Same with TP53, CDKN2A, MADH4, ARMET, ACVR1B, STK11 and RBBP8, KRAS gene also belongs to the somatic mutation genes of pancreatic cancer according to the Online Mendelian Inheritance in Man (OMIM) database. Research showed that KRAS mutation was an early event in pancreatic intraepithelial neoplasia (PanIN), and the subsequent mutations of TP53, CDKN2A, SMAD4 and other suppressor genes promoted early PanIN to advanced PanIN, and eventually to invasive pancreatic cancer (30). The amino acid sites accounting for the majority of mutations are G12, G13 and Q61, among which the most frequently mutations in pancreatic cancer are G12D and G12V. Whether there are significant differences between mutation types does not seem to be investigated, but overall, it has a promoting effect on both cancer development and dissemination, and the G12V mutation may be associated with the most aggressive phenotype (31). Sumimoto et al. demonstrated the necessity of RAS-mitogen-activated protein kinase signaling for upregulation of PD-L1 expression in human lung cancer (32), while Lastwika et al. identified the Akt-mTOR pathway as a regulator of PD-L1 expression in non-small cell lung cancer (33). In addition to that, KRAS activates a number of cytokines or chemokines, including tumor necrosis factor α (TNF-α), interleukin-1α/β (IL-1α/β), IL-6, CXCL1, 2, 5 and others, to promote inflammation, TME remodeling and immune evasion (34). These functions of the gene KRAS may explain some of the mechanisms of tumor progression and drug resistance in pancreatic cancer. A comprehensive understanding of pancreatic cancer gene mutations, the mechanism of anti-tumor drugs, and drug resistance causes could establish a theoretical basis for treating (Figure 8).

Figure 8 Gene mutation and drug action mechanisms in pancreatic cancer. Pharmacological and tumor resistance mechanisms, as well as potential interactions between albumin-bound paclitaxel, gemcitabine, and immune checkpoint inhibitor (PD-1 antagonists) in the KRAS-mutated pancreatic cancer. PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; ICI, immune checkpoint inhibitor; PSCs, pancreatic stellate cells; dFdC, 2’,2’-difluoro 2’-deoxycytidine (gemcitabine); TME, tumor microenvironment; SPARC, secreted protein acidic and rich in cysteine; ABC transporter, ATP-binding cassette transporter; hNTs, human nucleoside transporters; dC, deoxycytidine; dCK, deoxycytidine kinase; dFdCMP, gemcitabine monophosphate; dFdCDP, gemcitabine diphosphate; dFdCTP, gemcitabine triphosphate; CDA, cytidine deaminase; PI3K, phosphoinositide 3-kinase; TNF-α, tumor necrosis factor α; IL-1α/β, interleukin-1α/β; CXCL, C-X-C motif chemokine ligand; MDSCs, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages; T-regs, T-regulatory cells.

Conclusions

From this case report, it appears that the combination of chemotherapy and immunotherapy may be an effective treatment for some patients. However, there are some limitations in this study. Firstly, due to the absence of a control group and with only two reported cases, it is inconclusive whether the combination of PD-1 inhibitors and chemotherapy yields a significant therapeutic effect compared to chemotherapy alone. The potential underlying mechanisms require further exploration through basic experiments and clinical studies. Secondly, the pathological examination showed a small amount of residual high-grade intraepithelial neoplasia, which could potentially represent remaining viable cancer lesions within the stroma. The pursuit of more efficacious and less cytotoxic therapeutic alternatives for pancreatic cancer necessitates further investigation.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (grant Nos. 81974438, 81572783, and 81372239 to Y.C.).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-549/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-549/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-549/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). The research involving human participants were reviewed and approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (No. TJ-IRB20190418). Written informed consent was obtained from the patients for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Park W, Chawla A, O'Reilly EM. Pancreatic Cancer: A Review. JAMA 2021;326:851-62. [Crossref] [PubMed]
2. Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-21. [Crossref] [PubMed]
3. Hu ZI, O'Reilly EM. Therapeutic developments in pancreatic cancer. Nat Rev Gastroenterol Hepatol 2024;21:7-24. [Crossref] [PubMed]
4. Strobel O, Neoptolemos J, Jäger D, et al. Optimizing the outcomes of pancreatic cancer surgery. Nat Rev Clin Oncol 2019;16:11-26. [Crossref] [PubMed]
5. Deng A, Wang C, Cohen SJ, et al. Multi-agent neoadjuvant chemotherapy improves survival in early-stage pancreatic cancer: A National Cancer Database analysis. Eur J Cancer 2021;147:17-28. [Crossref] [PubMed]
6. Pancreatic Cancer. 2021. Available online: https://www.nccn.org/patients/
7. Del Chiaro M, Sugawara T, Karam SD, et al. Advances in the management of pancreatic cancer. BMJ 2023;383:e073995. [Crossref] [PubMed]
8. Neoptolemos JP, Kleeff J, Michl P, et al. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol 2018;15:333-48. [Crossref] [PubMed]
9. Do CTP, Prochnau JY, Dominguez A, et al. The Road Ahead in Pancreatic Cancer: Emerging Trends and Therapeutic Prospects. Biomedicines 2024;12:1979. [Crossref] [PubMed]
10. Yang SH, Kuo SH, Lee JC, et al. Adding-on nivolumab to chemotherapy-stabilized patients is associated with improved survival in advanced pancreatic ductal adenocarcinoma. Cancer Immunol Immunother 2024;73:227. [Crossref] [PubMed]
11. Zhang Z, Tang Y, Wang Y, et al. SIN3B Loss Heats up Cold Tumor Microenvironment to Boost Immunotherapy in Pancreatic Cancer. Adv Sci (Weinh) 2024;11:e2402244. [Crossref] [PubMed]
12. Wang B, Pan Y, Xie Y, et al. Metabolic and Immunological Implications of MME(+)CAF-Mediated Hypoxia Signaling in Pancreatic Cancer Progression: Therapeutic Insights and Translational Opportunities. Biol Proced Online 2024;26:29. [Crossref] [PubMed]
13. The Lancet Gastroenterology Hepatology. Pancreatic cancer: a state of emergency? Lancet Gastroenterol Hepatol 2021;6:81. [Crossref]
14. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
15. Mini E, Nobili S, Caciagli B, et al. Cellular pharmacology of gemcitabine. Ann Oncol 2006;17:v7-12. [Crossref] [PubMed]
16. Weaver BA. How Taxol/paclitaxel kills cancer cells. Mol Biol Cell 2014;25:2677-81. [Crossref] [PubMed]
17. Yardley DA. nab-Paclitaxel mechanisms of action and delivery. J Control Release 2013;170:365-72. [Crossref] [PubMed]
18. Frese KK, Neesse A, Cook N, et al. nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2012;2:260-9. [Crossref] [PubMed]
19. Gu J, Huang W, Wang X, et al. Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer. Mol Cancer 2022;21:112. [Crossref] [PubMed]
20. Yuan S, Xu J, Zhou B, et al. SOX8 Affects Tumoral SPARC Expression by Regulating EZH2 to Attenuate Effectiveness of albumin-bound paclitaxel in PDAC. Int J Biol Sci 2022;18:911-22. [Crossref] [PubMed]
21. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 2007;13:2151-7. [Crossref] [PubMed]
22. Chamoto K, Yaguchi T, Tajima M, et al. Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1. Nat Rev Immunol 2023;23:682-95. [Crossref] [PubMed]
23. Nagaraju GP, Malla RR, Basha R, et al. Contemporary clinical trials in pancreatic cancer immunotherapy targeting PD-1 and PD-L1. Semin Cancer Biol 2022;86:616-21. [Crossref] [PubMed]
24. Padrón LJ, Maurer DM, O'Hara MH, et al. Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial. Nat Med 2022;28:1167-77. [Crossref] [PubMed]
25. Chen Y, Guo C, Bai X, et al. Randomized phase II trial of neoadjuvant chemotherapy with modified FOLFIRINOX versus modified FOLFIRINOX and PD-1 antibody for borderline resectable and locally advanced pancreatic cancer (the CISPD-4 study). J Clin Oncol 2022;40:abstr 562.
26. Laheru D, Jaffee EM. Immunotherapy for pancreatic cancer - science driving clinical progress. Nat Rev Cancer 2005;5:459-67. [Crossref] [PubMed]
27. Fan JQ, Wang MF, Chen HL, et al. Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma. Mol Cancer 2020;19:32. [Crossref] [PubMed]
28. Dalin S, Sullivan MR, Lau AN, et al. Deoxycytidine Release from Pancreatic Stellate Cells Promotes Gemcitabine Resistance. Cancer Res 2019;79:5723-33. [Crossref] [PubMed]
29. Wang J, Yang J, Narang A, et al. Consensus, debate, and prospective on pancreatic cancer treatments. J Hematol Oncol 2024;17:92. [Crossref] [PubMed]
30. Luo J. KRAS mutation in pancreatic cancer. Semin Oncol 2021;48:10-8. [Crossref] [PubMed]
31. Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol 2020;17:153-68. [Crossref] [PubMed]
32. Sumimoto H, Takano A, Teramoto K, et al. RAS-Mitogen-Activated Protein Kinase Signal Is Required for Enhanced PD-L1 Expression in Human Lung Cancers. PLoS One 2016;11:e0166626. [Crossref] [PubMed]
33. Lastwika KJ, Wilson W 3rd, Li QK, et al. Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. Cancer Res 2016;76:227-38. [Crossref] [PubMed]
34. Hamarsheh S, Groß O, Brummer T, et al. Immune modulatory effects of oncogenic KRAS in cancer. Nat Commun 2020;11:5439. [Crossref] [PubMed]